Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 23, Pages 8148-8160Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm201071e
Keywords
-
Categories
Funding
- NIH/NIAID [HHSN272200900033C]
Ask authors/readers for more resources
Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cystein-yl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C-16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood,
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available